1. Field of the Invention
The present invention relates generally to macrocyclic expanded porphyrin compounds, and particularly, to the novel expanded porphyrin termed rubyrin and to a class of rubyrin analogues. Disclosed are rubyrin and rubyrin analogue compounds compositions, and methods of using protonated rubyrin compounds as anion chelators, receptors and transporters.
2. Description of the Related Art
In recent years increasing effort has been devoted to the preparation of novel "expanded porphyrins".sup.1, large pyrrole-containing macrocyclic analogues of the porphyrins (e.g. porphine, FIG. 1A) and a number of such systems are now known.sup.1-17. However, only a few fully conjugated examples have been reported that contain more than four pyrrolic subunits, namely the smaragdyrins.sup.2,3 sapphyrins.sup.2-6, pentaphyrins.sup.7,8, hexaphyrins.sup.9 and superphthalocyanines.sup.10. These compounds are represented in their generalized substituent-free forms as FIG. 1B-FIG. 1F).
To date, there remains relatively little documented information concerning the chemistry of the above-mentioned expanded porphyrin systems. Indeed, at present, structural information is available only for derivatives of sapphyrin (e.g. FIG. 1B).sup.4,5 and pentaphyrin (e.g. FIG. 1C).sup.8 in the all-pyrrole series. Therefore, numerous fundamental questions concerning these molecules still remain to be answered, such as those pertaining to ring size, aromaticity, and effective macrocycle stability. The synthesis and structural characterization of hexapyrrolic macrocycles would be a particular advance in this area, allowing the answers to such inter-related questions to be elucidated.
It has long been appreciated that a considerable number of ionic (e.g. phosphorylated) nucleotide analogues exhibit antiviral activity in cell-free extracts, yet are inactive in vivo due to their inability to cross lipophilic cell membranes.sup.25,26. For example, the anti-herpetic agent, acyclovir (FIG. 9A, structure a; 9-[(2-hydroxyethoxy)methyl]-9H-guanine), is typical in that it is able to enter the cell only in its uncharged nucleoside-like form. Upon gaining entry to the cytoplasm it is phosphorylated, first by a viral-encoded enzyme, thymidine kinase (FIG. 9A, structure b), and then by relatively nonspecific cellular enzymes to produce the active, ionic triphosphate nucleotide-like species (FIG. 9A, structure c). There it functions both as an inhibitor of the viral DNA polymerase and as a chain terminator for newly synthesized herpes simplex DNA.
Many other potential antiviral agents, including, for instance, the anti-HIV agent, Xylo-G (FIG. 9B; structure d) 9-(.beta.-D-xylofuranosyl)guanine), on the other hand, are not phosphorylated by a viral enzyme and are, therefore, largely or completely inactive.sup.27. If, however, the active monophosphorylated forms of these putative drugs (such as in FIG. 9B, structure e) could be transported into cells, it would be possible to fight viral infections with a large battery of otherwise inactive materials. If such specific into-cell transport were to be achieved, it would therefore greatly augment the treatment of such debilitating diseases as, for example, AIDS, herpes, hepatitis and measles. Given the fact that AIDS is currently a major national health problem of frightening proportions, and that something so nominally benign as measles still claims over 100,000 lives per year world-wide.sup.26, treatment of these diseases would be particularly timely and worthwhile.
At present, no general set of nucleotide transport agents exists. In early work, Tabushi was able to effect adenosine nucleotide transport using a lipophilic, diazabicyclooctane-derived, quaternary amine system.sup.28. However, this same system failed to mediate the transport of guanosine 5'-monophosphate (GMP) or other guanosine-derived nucleotides. Since then, considerable effort has been devoted to the generalized problem of nucleic acid base ("nucleobase") recognition, and various binding systems have been reported.
Currently known nucleotide binding systems include acyclic, macrocyclic, and macrobicyclic polyaza systems.sup.29-37 ; nucleotide-binding bis-intercalands.sup.38 ; guanidinium-based receptors.sup.39-46 ; and various rationally designed H-bonding receptors.sup.47-53. These latter H-bonding receptors have been shown to be effective for the chelation of neutral nucleobase and/or nucleoside derived substrates but, without exception, have also all proved unsatisfactory for the important task of charged nucleotide recognition. Large macrocyclic compounds, particularly macrocyclic compounds larger than sapphyrins, which could be relatively easily protonated could prove to be useful in anion binding and transport.
Despite intensive efforts in this field, there is currently no synthetic system capable of effecting the recognition and through-membrane transport of phosphate-bearing species such as anti-viral compounds. Furthermore, there are presently no rationally designed receptors which are "tunable" for the selective complexation of a given nucleobase-derived system.
There is clearly, therefore, a major need for novel drug delivery systems to be developed. Compounds which would allow negatively-charged (anionic) structures, particularly specifically-recognized nucleotides, to be transported across naturally lipophilic cellular membranes would represent an important scientific and medical advance. The development of such anion carriers may also prove to be important in the clinical treatment of cystic fibrosis, in that such compounds would likely facilitate the out-of-cell diffusion of chloride anions.